1. Field of the Invention
The present invention relates to an anti-inflammatory agent, especially to an anti-inflammatory agent against inflammation such as protracted inflammation (chronic progressive inflammation) or inflammation in which immunological mechanism participates.
More specifically, the present invention relates to a potentiator of immunosuppressant potentiating anti-inflammatory effect thereof or an agent enhancing anti-inflammatory effect.
According to the present invention, the onset and/or progress of diseases, such as glomerulonephritis, collagen diseases or related diseases thereof, intractable angiitis, immunological anomalies accompanied with inflammation or autoimmune diseases etc. can be prevented or treated.
2. Description of the Background
Inflammation in which immunological mechanism participates, for example, glomerulonephritis, collagen diseases or related diseases, intractable angiitis, immunological anomalies accompanied with inflammation or autoimmune diseases etc. chronically progresses by repeating acute exacerbation and, without treatment, causes organ deterioration, resulting in renal failure or other organ failures and eventually death. Most of such a chronic progressive inflammation are intractable the causes of the onset thereof have been thought to be immunological anomalies and continuous activation of inflammatory mediator accompanied therewith. Various kinds of therapy have been investigated focusing on these causes. For example, with respect to immunological anomalies, an immunosuppressant such as adrenocorticosteroid, cyclophosphamide, mizoribine, methotrexate or azathioprine is used in a usual manner or in salvage intravenous infusion therapy (pulse therapy). However, adrenocorticosteroid shows serious adverse effects such as suppressive action on adrenal function, easy infectiousness, peptic ulcer, hypertension, osteoporosis and so on. In addition, other immunosuppressants also show extremely serious adverse effects such as bone marrow suppression, onset of gastrointestinal disorders, liver damages, interstitial pneumonia, renal disorders or hemorrhagic urocystitis and so on. In addition, since this kind of pharmacotherapy is not an etiotropic therapy and is carried out by administrating an agent for long duration to cause serious adverse effects, it will cause extremely serious problems. Further, some of those diseases are drug-resistant. Against diseases whose main lesions are nephritis or angiitis, an anti-platelet agent or an anti-coagulant can be used. However, whenever an anti-coagulant such as heparin or warfarin (trade name;general name, Warfarin potassium) is used, hemorrhage has to be cared as an adverse effect. As for an anti-platelet agent, risk of hemorrhage has to be considered. Because among collagen diseases, there are many patients with decreased level of platelet such as in the case of systemic lupus erythematosus (SLE) or many patients with pulmonary hemorrhage such as in the case of Good pasture syndrome accompanied with glomerulonephritis it is difficult to use an anti-platelet agent in such a case as above. Further, though it was reported recently that heparin or low molecular weight heparin was effective for preventing nephritis accompanied with SLE (Japanese unexamined patent application 40327/1990, Arthritis Rheum. 33, 1554, 1990), the effect was not so sure according to the experimental result by the present inventors as described later.
It is an object of the present invention to provide a pharmaceutical composition containing glycosaminoglycan having at least one sulfate group or a pharmaceutically acceptable salt thereof, and an immunosuppressant.
Inflammation in which immunological mechanism participates, such as, glomerulonephritis, collagen diseases or related diseases thereof, intractable angiitis, immunological anomalies accompanied with inflammation, or autoimmune diseases comprises SLE described above. By considering the above situation and investigating an action of dermatan sulfate or pharmaceutically acceptable salt thereof on these inflammatory diseases using MRL (Ipr/lpr) mice (lzui S., et al., Mechanism of genetic control of murine systemic lupus erythematosus. In systemic Lupus Erythematosus, pp. 3-12, Ed. Peter A. Miescher, Springer-Verlag Berlin, 1995) as an animal model of SLE, the present inventors found that the compound not only suppressed inflammation and delayed the progress of disease, but also had an excellent safety and can be used for a long duration. Further, the effect of dermatan sulfate was investigated using animal model of human multiple sclerosis, rat with experimental allergic encephalomyelitis as another example of inflammation in which immunological mechanism participates, and found to be effective for these diseases. A certain type of dermatan sulfate with specific physical properties or with specific origin, or pharmacologically acceptable salt thereof among various types of dermatan sulfate was found to keep serum level thereof for longer duration and be preferable. That is, dermatan sulfate or pharmaceutically acceptable salt thereof suitable for practice of the present invention was found to be one comprising 2-9%, preferably 3-8%, of Di-OS (xcex94HexA1xe2x86x923GalNAc); with 0.8-2.0 of intrinsic viscosity (100 mL/g); with 25,000-100,000, preferably 30,000-60,000, of molecular weight which was determined by gel permeation method using high performance liquid chromatography and glycosaminoglycan whose molecular weight was known as a standard (see reference example 1, (1)Determination of molecular weight which was described in Biochim. Biophys. Acta, 1117, 60-70, 1992); or dermatan sulfate derived from crest. The present invention was accomplished by these observations.
An object of the present invention is to provide an anti-inflammatory agent having an excellent anti-inflammatory effect on inflammation using an action of dermatan sulfate or pharmaceutically acceptable salt, especially effective for prevention or treatment of intractable inflammation such as glomerulonephritis, which is inflammation related with immunological mechanism or protracted inflammation, collagen diseases or related diseases thereof intractable angiitis, immunological anomalies accompanied with inflammation, or autoimmune diseases. Another object of the present invention is to provide an agent enhancing anti-inflammatory effect of immunosuppressant in combination with glycosaminoglycan having sulfate group.
The present invention relates to an anti-inflammatory agent comprising dermatan sulfate or pharmaceutically acceptable salt thereof as an effective ingredient as described above. Specifically, the present invention relates to an anti-inflammatory agent comprising dermatan sulfate as an effective ingredient which exhibit an anti-inflammatory effect on protracted inflammation or inflammation with immunological mechanism such as inflammation accompanied with autoimmune diseases. The present invention, more specifically, relates to an anti-inflammatory agent useful for inflammation accompanied with multiple sclerosis, collagen diseases or related diseases thereof, glomerulonephritis, intractable angiitis and the like. In addition, the present invention relates to an anti-inflammatory agent comprising dermatan sulfate with specific physical properties or with specific origin or pharmaceutically acceptable salt thereof. Further, the present invention relates to an enhancing agent which enhances anti-inflammatory effect of an immunosuppressant and comprises glycosaminoglycan having sulfate group or pharmaceutically acceptable salt thereof as an effective ingredient. Further, the present invention relates to an agent enhancing anti-inflammatory effect of an immunosuppressant which comprises glycosaminoglycan having sulfate group or pharmaceutically acceptable salt thereof and an immunosuppresing compound (immunosuppressant).
As glycosaminoglycan having sulfate group which is used in combination with an immunosuppressant, dermatan sulfate, heparin, heparan sulfate, chondroitin sulfate and keratan sulfate are exemplified. Among them, dermatan sulfate is preferable and dermatan sulfate with specific physical properties or with specific origin as described above or pharmaceutically acceptable salt thereof is more preferable.